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BMC Cancer May 2022Whether pioglitazone may affect breast cancer risk in female diabetes patients is not conclusive and has not been investigated in the Asian populations.
BACKGROUND
Whether pioglitazone may affect breast cancer risk in female diabetes patients is not conclusive and has not been investigated in the Asian populations.
METHODS
The reimbursement database of Taiwan's National Health Insurance was used to enroll an unmatched cohort and a propensity score-matched cohort of ever users and never users of pioglitazone in female patients with newly diagnosed type 2 diabetes during 1999-2008. The patients were alive on January 1, 2009 and were followed up for breast cancer incidence until December 31, 2011. Cox regression was used to estimate hazard ratios for ever users and tertiles of cumulative duration of pioglitazone therapy versus never users, and for cumulative duration of pioglitazone therapy treated as a continuous variable. Three models were created for the unmatched cohort and the matched cohort, respectively: 1) without adjustment for covariates; 2) after adjustment for covariates that differed with statistical significance (P-value < 0.05) between ever users and never users; and 3) after adjustment for all covariates.
RESULTS
There were 174,233 never users and 6926 ever users in the unmatched cohort; and 6926 never users and 6926 ever users in the matched cohort. After a median follow-up of 2.8 years, the numbers of incident breast cancer were 1044 in never users and 35 in ever users in the unmatched cohort and were 41 and 35, respectively, in the matched cohort. Hazard ratios suggested a null association between pioglitazone and breast cancer in all three models in either the unmatched cohort or the matched cohort. The overall hazard ratio after adjustment for all covariates was 0.758 (95% confidence interval: 0.539-1.065) in the unmatched cohort and was 0.824 (95% confidence interval: 0.524-1.296) in the matched cohort. None of the hazard ratios for the tertiles of cumulative duration of pioglitazone therapy and for the cumulative duration being treated as a continuous variable were statistically significant.
CONCLUSIONS
This study suggests a null association between pioglitazone and breast cancer risk in female patients with type 2 diabetes mellitus. However, because of the small breast cancer cases and the limited follow-up time, further studies are warranted to confirm our findings.
Topics: Breast Neoplasms; Cohort Studies; Diabetes Mellitus, Type 2; Female; Humans; Hypoglycemic Agents; Incidence; Metformin; Pioglitazone; Proportional Hazards Models; Retrospective Studies; Risk Factors; Taiwan
PubMed: 35585577
DOI: 10.1186/s12885-022-09660-8 -
Ugeskrift For Laeger Jul 2018Non-alcoholic fatty liver disease and especially non-alcoholic steatohepatitis (NASH) and fibrosis are associated with severe liver disease and increased cardiovascular... (Review)
Review
Non-alcoholic fatty liver disease and especially non-alcoholic steatohepatitis (NASH) and fibrosis are associated with severe liver disease and increased cardiovascular risk. It is therefore important to identify patients with NASH fibrosis. Therapeutical options include life style intervention and pharmacological treatment with vitamin E and pioglitazone; however, evidence of effect is scarce for all options. New treatments are under investigation and include glucagon-like peptide-1, farnesoid receptor as well as peroxisome proliferator-activated receptor-α/δ agonists. Bariatric surgery may be an option in selected patients.
Topics: Bariatric Surgery; Chalcones; Chenodeoxycholic Acid; Critical Pathways; Humans; Hypoglycemic Agents; Life Style; Liraglutide; Non-alcoholic Fatty Liver Disease; Pioglitazone; Propionates; Risk Assessment; Vitamin E
PubMed: 30064623
DOI: No ID Found -
Biochimica Et Biophysica Acta.... Jul 2023Podocytes are specialized epithelial cells that maintain the glomerular filtration barrier. These cells are susceptible to lipotoxicity in the obese state and...
Podocytes are specialized epithelial cells that maintain the glomerular filtration barrier. These cells are susceptible to lipotoxicity in the obese state and irreversibly lost during kidney disease leading to proteinuria and renal injury. PPARγ is a nuclear receptor whose activation can be renoprotective. This study examined the role of PPARγ in the lipotoxic podocyte using a PPARγ knockout (PPARγKO) cell line and since the activation of PPARγ by Thiazolidinediones (TZD) is limited by their side effects, it explored other alternative therapies to prevent podocyte lipotoxic damage. Wild-type and PPARγKO podocytes were exposed to the fatty acid palmitic acid (PA) and treated with the TZD (Pioglitazone) and/or the Retinoid X receptor (RXR) agonist Bexarotene (BX). It revealed that podocyte PPARγ is essential for podocyte function. PPARγ deletion reduced key podocyte proteins including podocin and nephrin while increasing basal levels of oxidative and ER stress causing apoptosis and cell death. A combination therapy of low-dose TZD and BX activated both the PPARγ and RXR receptors reducing PA-induced podocyte damage. This study confirms the crucial role of PPARγ in podocyte biology and that their activation in combination therapy of TZD and BX may be beneficial in the treatment of obesity-related kidney disease.
Topics: Humans; PPAR gamma; Podocytes; Pioglitazone; Thiazolidinediones; Kidney Diseases; Bexarotene
PubMed: 37156296
DOI: 10.1016/j.bbalip.2023.159329 -
International Journal of Nanomedicine 2023Hyaluronic acid (HA) is a popular biological material for osteoarthritis (OA) treatment. Pioglitazone, a PPAR-γ agonist, has been found to inhibit OA, but its use is...
BACKGROUND
Hyaluronic acid (HA) is a popular biological material for osteoarthritis (OA) treatment. Pioglitazone, a PPAR-γ agonist, has been found to inhibit OA, but its use is limited because achieving the desired local drug concentration after administration is challenging.
PURPOSE
Herein, we constructed HA-based cartilage-targeted nanomicelles (C-HA-DOs) to deliver pioglitazone in a sustained manner and evaluated their efficacy in vitro and in vivo.
METHODS
C-HA-DOs were chemically synthesized with HA and the WYRGRL peptide and dodecylamine. The products were characterized by FT-IR, H NMR, zeta potential and TEM. The drug loading rate and cumulative, sustained drug release from Pio@C-HA-DOs were determined, and their biocompatibility and effect on oxidative stress in chondrocytes were evaluated. The uptake of C-HA-DOs by chondrocytes and their effect on OA-related genes were examined in vitro. The nanomicelle distribution in the joint cavity was observed by in vivo small animal fluorescence imaging (IVIS). The therapeutic effects of C-HA-DOs and Pio@C-HA-DOs in OA rats were analysed histologically.
RESULTS
The C-HA-DOs had a particle size of 198.4±2.431 nm, a surface charge of -8.290±0.308 mV, and a critical micelle concentration of 25.66 mg/Land were stable in solution. The cumulative drug release from the Pio@C-HA-DOs was approximately 40% at pH 7.4 over 24 hours and approximately 50% at pH 6.4 over 4 hours. Chondrocytes rapidly take up C-HA-DOs, and the uptake efficiency is higher under oxidative stress. In chondrocytes, C-HA-DOs, and Pio@C-HA-DOs inhibited HO-induced death, reduced intracellular ROS levels, and restored the mitochondrial membrane potential. The IVIS images confirmed that the micelles target cartilage. Pio@C-HA-DOs reduced the degradation of collagen II and proteoglycans by inhibiting the expression of MMP and ADAMTS, ultimately delaying OA progression in vitro and in vivo.
CONCLUSION
Herein, C-HA-DOs provided targeted drug delivery to articular cartilage and improved the role of pioglitazone in the treatment of OA.
Topics: Rats; Animals; Hyaluronic Acid; Pioglitazone; Hydrogen Peroxide; Spectroscopy, Fourier Transform Infrared; Osteoarthritis; Chondrocytes; Cartilage, Articular
PubMed: 37873552
DOI: 10.2147/IJN.S428938 -
Biochemical and Biophysical Research... Aug 2023Iron-sulfur clusters play a central role in cellular function and are regulated by the ATM protein. Iron-sulfur clusters are part of the cellular sulfide pool, which...
BACKGROUND
Iron-sulfur clusters play a central role in cellular function and are regulated by the ATM protein. Iron-sulfur clusters are part of the cellular sulfide pool, which functions to maintain cardiovascular health, and consists of free hydrogen sulfide, iron-sulfur clusters, protein bound sulfides, which constitute the total cellular sulfide fraction. ATM protein signaling and the drug pioglitazone share some cellular effects, which led us to examine the effects of this drug on cellular iron-sulfur cluster formation. Additionally, as ATM functions in the cardiovasculature and its signaling may be diminished in cardiovascular disease, we examined pioglitazone in the same cell type, with and without ATM protein expression.
METHODS
We examined the effects of pioglitazone treatment on the total cellular sulfide profile, the glutathione redox state, cystathionine gamma-lyase enzymatic activity, and on double-stranded DNA break formation in cells with and without ATM protein expression.
RESULTS
Pioglitazone increased the acid-labile (iron-sulfur cluster) and bound sulfur cellular fractions and reduced cystathionine gamma-lyase enzymatic activity in cells with and without ATM protein expression. Interestingly, pioglitazone also increased reduced glutathione and lowered DNA damage in cells without ATM protein expression, but not in ATM wild-type cells. These results are interesting as the acid-labile (iron-sulfur cluster), bound sulfur cellular fractions, and reduced glutathione are low in cardiovascular disease.
CONCLUSION
Here we found that pioglitazone increased the acid-labile (iron-sulfur cluster) and bound sulfur cellular fractions, impinges on hydrogen sulfide synthesis, and exerts beneficial effect on cells with deficient ATM protein signaling. Thus, we show a novel pharmacologic action for pioglitazone.
Topics: Humans; Hydrogen Sulfide; Ataxia Telangiectasia Mutated Proteins; Pioglitazone; Cystathionine gamma-Lyase; Cardiovascular Diseases; Sulfides; Sulfur; Glutathione; Iron; Iron-Sulfur Proteins
PubMed: 37285721
DOI: 10.1016/j.bbrc.2023.05.118 -
PloS One 2022There is limited information on the efficacy of pioglitazone in diabetic kidney diseases (DKD). We evaluated whether pioglitazone exerts renal-protective effects in DKD...
There is limited information on the efficacy of pioglitazone in diabetic kidney diseases (DKD). We evaluated whether pioglitazone exerts renal-protective effects in DKD patients. We designed a retrospective cohort study, which included 742 type 2 diabetes mellitus (T2DM) patients with DKD in Taiwan, with eGFR between 30 and 90 ml/min/1.73 m2 and UACR level 300-5000 mg/g. Patients not meeting the target range for HbA1c (above 7%) were given additional medication with pioglitazone (n = 111) or received standard care (non-pioglitazone group, n = 631). The primary endpoint was the occurrence of composite renal endpoints, which was defined as sustained eGFR<15 ml/min/1.73 m2 (confirmed by two measurements within 90 days); doubling of serum creatinine (compared to baseline); and the presence of hemodialysis or renal transplantation. The median follow-up duration was two years. At baseline, the mean HbA1C levels in the pioglitazone and non-pioglitazone groups were 8.8% and 8.1%, respectively; mean ages were 64.4 and 66.2 years old, respectively; diabetes durations were 14.3 and 12.3 years, respectively. Baseline eGFR showed no significant difference between the pioglitazone and non-pioglitazone groups (55.8 and 58.8 mL/min/1.73 m2, respectively). In terms of gender, 63% of patients were male in the pioglitazone group compared with 57% in the non-pioglitazone group. Pioglitazone use did not reduce the risk of composite renal endpoints in DKD patients (HR: 0.97, 95% CI = 0.53-1.77), including persistent eGFR<15 ml/min/1.73 m2 (HR = 1.07, 95% CI = 0.46-2.52), doubling of serum creatinine (HR = 0.97, 95% CI = 0.53-1.77), or ESRD (HR = 2.58, 95% CI = 0.29-23.04). The results were not changed after various adjustments. A non-significant albuminuria reduction was also noted after pioglitazone prescription in DKD patients. Further randomized controlled studies are needed to establish the effects of pioglitazone definitively.
Topics: Aged; Albuminuria; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Glomerular Filtration Rate; Humans; Hypoglycemic Agents; Kidney; Male; Middle Aged; Pioglitazone; Retrospective Studies; Taiwan
PubMed: 35176115
DOI: 10.1371/journal.pone.0264129 -
Pharmacoepidemiology and Drug Safety Oct 2022National regulators in Australia and the United Kingdom issued safety advisories on the association between pioglitazone use and bladder cancer in July 2011. The...
PURPOSE
National regulators in Australia and the United Kingdom issued safety advisories on the association between pioglitazone use and bladder cancer in July 2011. The Australian advisory noted that males were at higher risk of bladder cancer than females, while the UK advisory highlighted a new recommendation, suggest careful consideration in the elderly due to increasing risk with age. This study examined whether these differences in the advisories had different age- and sex-based impacts in each country.
METHODS
Interrupted time series analysis was used to compare pioglitazone use (prescriptions/100000 population) in Australia and the United Kingdom for the 24 months before and 11 months after the July 2011 safety advisories (study period July 2009-June 2012). Separate models were used to compare use by sex and age group (≥65 years vs. <65 years) in each country.
RESULTS
Pioglitazone use fell in Australia (17%) and the United Kingdom (24%) following the safety advisories. Use of pioglitazone fell more for males (18%) than females (16%) in Australia, and more for females (25%) than males (23%) in the United Kingdom; however, neither difference was statistically significant (Australia p = 0.445, United Kingdom p = 0.462). Pioglitazone use fell to a similar extent among older people than younger people in the United Kingdom (23% vs. 26%, p = 0.354), and did not differ between age groups in Australia (both 18%, p = 0.772).
CONCLUSIONS
The results indicate that differences in the Australian and UK safety advisories resulted in substantial reductions in pioglitazone use at the population level in both countries, however, differences by sub-groups were not observed.
Topics: Aged; Australia; Diabetes Mellitus, Type 2; Female; Humans; Hypoglycemic Agents; Interrupted Time Series Analysis; Male; Pioglitazone; Thiazolidinediones; United Kingdom; Urinary Bladder Neoplasms
PubMed: 35790047
DOI: 10.1002/pds.5508 -
Alimentary Pharmacology & Therapeutics Sep 2017Non-alcoholic fatty liver disease is the fastest growing cause of liver disease in the Western world, yet there is no approved pharmacotherapy. While lifestyle... (Review)
Review
BACKGROUND
Non-alcoholic fatty liver disease is the fastest growing cause of liver disease in the Western world, yet there is no approved pharmacotherapy. While lifestyle modifications remain the mainstay of treatment, only a proportion of individuals are able to make or sustain them, and so more treatment options are required.
AIM
To review the potential benefit of drugs used in clinical practice, those entering phase II trials, and compounds being investigated in pre-clinical studies.
METHODS
A literature search was performed using PubMed to identify relevant studies; linked references were also reviewed.
RESULTS
Vitamin E and pioglitazone have shown efficacy in non-alcoholic steatohepatitis (NASH), but long-term safety concerns, specifically bladder cancer and osteoporosis with pioglitazone, have limited their use. GLP-1 analogues and SGLT-2 inhibitors are currently approved for use in diabetes, have shown early efficacy in NASH and also have beneficial cardiovascular effects. Peroxisome proliferator-activator receptors and FXR agonists have potent effects on lipogenesis, inflammation and fibrosis, respectively, with their efficacy and safety being currently tested in phase 3. As inflammation and apoptosis are key features of NASH agents modulating these pathways are of interest; CCR2/5 antagonists downregulate inflammatory pathways and reduce fibrosis with caspase and apoptosis signal-regulating kinase 1 inhibitors reducing apoptosis and fibrosis.
CONCLUSIONS
Rising demand and an improved understanding of NASH pathophysiology has led to a surge in development of new therapies. Tailoring pharmacotherapy to the dominant pathogenic pathway in a given patient along with use of combination therapy is likely to represent the future direction in treatment of patients with NASH.
Topics: Drug Design; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; MAP Kinase Kinase Kinase 5; Non-alcoholic Fatty Liver Disease; Pioglitazone; Thiazolidinediones; Vitamin E
PubMed: 28677333
DOI: 10.1111/apt.14210 -
International Journal of Environmental... Dec 2022Thiazolidinediones (TZDs) are a group of diabetes medications currently being investigated for anti-arthritis effectiveness, one of which is pioglitazone. The purpose of... (Review)
Review
Thiazolidinediones (TZDs) are a group of diabetes medications currently being investigated for anti-arthritis effectiveness, one of which is pioglitazone. The purpose of this scoping review is to evaluate the potential use of pioglitazone in the treatment of temporomandibular joint (TMJ) arthritis. The criteria of eligibility were studies with the diagnosis of arthritis and pioglitazone treatment with a change in any inflammation index as an outcome. Of the 1169 records initially identified following the selection process, two animal studies and four clinical studies were included in the review. Improvements from the baseline were observed in each treatment group for each inflammation indicator. The results of the animal studies on the temporomandibular joints and on patients with rheumatoid and psoriatic arthritis indicate that the drug in question may have potential to treat arthritis, including within the temporomandibular joint.
Topics: Animals; Pioglitazone; Arthritis, Rheumatoid; Temporomandibular Joint; Temporomandibular Joint Disorders; Inflammation
PubMed: 36554400
DOI: 10.3390/ijerph192416518 -
Frontiers in Endocrinology 2022Understanding which group of patients with type 2 diabetes will have the most glucose lowering response to certain medications (which target different aspects of glucose... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Understanding which group of patients with type 2 diabetes will have the most glucose lowering response to certain medications (which target different aspects of glucose metabolism) is the first step in precision medicine.
AIMS
We hypothesized that people with type 2 diabetes who generally have high insulin resistance, such as people of Māori/Pacific ethnicity, and those with obesity and/or hypertriglyceridemia (OHTG), would have greater glucose-lowering by pioglitazone (an insulin sensitizer) versus vildagliptin (an insulin secretagogue).
METHODS
A randomised, open-label, two-period crossover trial was conducted in New Zealand. Adults with type 2 diabetes, HbA1c>58mmol/mol (>7.5%), received 16 weeks of either pioglitazone (30mg) or vildagliptin (50mg) daily, then switched to the other medication over for another 16 weeks of treatment. Differences in HbA1c were tested for interaction with ethnicity or OHTG, controlling for baseline HbA1c using linear mixed models. Secondary outcomes included weight, blood pressure, side-effects and diabetes treatment satisfaction.
RESULTS
346 participants were randomised (55% Māori/Pacific) between February 2019 to March 2020. HbA1c after pioglitazone was lower than after vildagliptin (mean difference -4.9mmol/mol [0.5%]; 95% CI -6.3, -3.5; p<0.0001). Primary intention-to-treat analysis showed no significant interaction effect by Māori/Pacific vs other ethnicity (1.5mmol/mol [0.1%], 95% CI -0.8, 3.7), and per-protocol analysis (-1.2mmol/mol [0.1%], 95% CI -4.1, 1.7). An interaction effect (-4.7mmol/mol [0.5%], 95% CI -8.1, -1.4) was found by OHTG status. Both treatments generated similar treatment satisfaction scores, although there was greater weight gain and greater improvement in lipids and liver enzymes after pioglitazone than vildagliptin.
CONCLUSIONS
Comparative glucose-lowering by pioglitazone and vildagliptin is not different between Māori/Pacific people compared with other New Zealand ethnic groups. Presence of OHTG predicts greater glucose lowering by pioglitazone than vildagliptin.
CLINICAL TRIAL REGISTRATION
www.anzctr.org.au, identifier (ACTRN12618001907235).
Topics: Adult; Humans; Vildagliptin; Pioglitazone; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Dipeptidyl-Peptidase IV Inhibitors; Glycated Hemoglobin; Glucose; Cross-Over Studies; Thiazolidinediones; Nitriles; Pyrrolidines; Obesity; Hypertriglyceridemia
PubMed: 36699039
DOI: 10.3389/fendo.2022.1091421